Gallbladder Cancer

Authors
Shiva Kumar R. Mukkamalla1; Sarang Kashyap2; Alejandro Recio-Boiles3; Hani M. Babiker4.

Affiliations
1
 Presbyterian Healthcare Services
2
 Beckley Appalachian Regional Healthcare Hospital
3
 University of Arizona
4
 University of Arizona Cancer Center

Last Update: January 15, 2023.

Continuing Education Activity

Gallbladder cancer (GC) is a rare malignancy but represents almost 50% of all biliary tract
cancer. Biliary cancers are highly fatal malignancies with a 5-year survival rate of 17.6%
(2007-2013). The prognosis of gallbladder cancer is poor due to the aggressive tumor
biology, late presentation, complicated anatomic position, and advanced stage at diagnosis.
Locally advanced and metastatic disease is treated with palliative chemotherapy. Conversely,
early stage is potentially curative with surgical resection followed by adjuvant therapy. This
activity reviews the evaluation of gallbladder cancer and the role of the interprofessional
team in caring for patients with this condition.
Objectives:
 Describe the frequency of gallbladder cancer.
 Review the treatment of locally advanced gallbladder cancer.
 Outline the treatment of early stage gallbladder cancer.
 Summarize the evaluation of gallbladder cancer and the role of the interprofessional
team in caring for patients with this condition.
Access free multiple choice questions on this topic.

Introduction
Gallbladder cancer (GC) is a rare malignancy but represents almost 50% of all biliary tract
cancer.[1] Biliary cancers are highly fatal malignancies with a 5-year survival rate of 17.6%
(2007 to 2013)[2]. The prognosis of gallbladder cancer is poor due to the aggressive tumor
biology, late presentation, complicated anatomic position, and advanced stage at diagnosis.
Locally advanced and metastatic disease treatment is with palliative chemotherapy.
Conversely, early-stage is potentially curative with surgical resection followed by adjuvant
therapy.

Etiology
Chronic inflammation is the most critical risk of gallbladder cancer.[3] The strongest
correlation to develop gallbladder cancer is a history of gallstones (cholelithiasis), and
the risk increases with gallstone size, chronicity, and burden of symptoms. Porcelain
gallbladder, a calcification of the gallbladder, is often related to chronic cholelithiasis. This
condition is usually found incidentally on imaging and often leads to cholecystectomy. The
other risk factors include gallbladder polyps, congenital biliary cysts, and abnormal
pancreaticobiliary anatomy, which all lead to chronic inflammation culminating in
gallbladder cancer. Endemic areas with salmonella typhi and helicobacter report a link with
chronic asymptomatic carriers and an elevated risk for gallbladder cancer. Moreover,
carcinogens causing gallbladder cancer include (e.g., methyldopa, isoniazid), work exposure
(e.g., methylcellulose, radon), and lifestyle (e.g., cigarette smoking, obesity, high
carbohydrate intake). Chronic primary sclerosing cholangitis and inflammatory bowel disease
can also lead to gallbladder cancer.

Epidemiology
The incidence of gallbladder cancer is high in specific populations outside of the United
States (e.g., South America, India, Pakistan, Japan, and Korea) due to the high prevalence of
gallstones and chronic gallbladder infections in those areas. The American Cancer Society
estimates 11,740 new cases of gallbladder cancer and 3,830 deaths in the USA with a female
preponderance in 2017. The overall incidence of gallbladder cancer decreased
in patients older than 50 years but increased in the younger population. Gallbladder cancer is
more common in Whites, Southwestern Native Americans, and Mexican Americans and less
common in African Americans.

Pathophysiology
The current hypothesis establishes that chronic inflammation of the bile duct tissue
accumulates successive genomic mutations that lead to malignant transformation. The most
common mutations described are the oncogenes K-ras and tumor suppressors beta-catenin
(CTNNB1).[4] Research has not revealed any hereditary familial risk. Most of the
histopathology changes in gallbladder cancer appear as adenocarcinomas (90%). This
condition progresses from pre-neoplastic dysplasia to carcinoma in situ and, ultimately, to
invasive cancer, following roughly 15 years of inflammation. Squamous cell carcinoma is
rare in the gallbladder.

History and Physical

Gallbladder cancer detection often occurs as an incidental finding on imaging or after a
surgical procedure. Early-stage gallbladder cancer is commonly discovered after
cholecystectomy and review of the surgical pathology specimen. 
Gallbladder cancer patients are often asymptomatic at presentation or describe vague
symptoms such as abdominal pain, nausea or vomiting, indigestion, weakness, anorexia, loss
of appetite, weight loss, and can present with jaundice, which can easily be confused as
cholecystitis. Biliary obstruction by cancer leads to jaundice, clay-colored stools, cola-
colored urine, and skin pruritus. Also, Mirizzi syndrome (common hepatic duct obstruction
by an impacted stone in the gallbladder neck due to an extrinsic compression) has shown an
association with gallbladder cancer. It carries a poor prognosis due to unresectability at
presentation[5]. Other unspecific symptoms of advanced malignancy, such as weight loss and
general malaise, may also be present.
Physical examination may demonstrate jaundice, right upper quadrant pain, or Courvoisier
sign (non-tender palpable gallbladder with jaundice), which is most likely to develop due to
chronic progressive malignant obstruction rather than an intermittent gallstone obstruction.
Hepatomegaly, abdominal palpable mass, ascites, and bowel obstruction on physical
examination are presentations that indicate advanced metastatic stage.

Evaluation
Patients, particularly those with obstructive jaundice, will require complete blood count, basic
chemistry panel, and a liver function test. Results may reveal an unspecific cholestatic pattern
caused by bile obstruction requiring decompression. Ultrasonography (US) and computed
tomography (CT) are usually the initial imaging studies. Endoscopic ultrasonography (EUS)
is considered more accurate than ultrasound (76%) and useful in differential diagnosis to
detect histological neoplasia correctly (97%). EUS will provide a valuable tumor-stage
description with invasion depth and local lymphadenopathy. CT has limitations in
discriminating benign from malignant, but dynamic magnetic resonance (MR) and MR
cholangiopancreatography (MRCP) can help assess disease extent more accurately and
properly identify unresectable candidates with hepatoduodenal ligament invasion, vasculature
encasement, and/or lymph node involvement.[6] Most gallbladder cancers are 18F-
fluorodeoxyglucose avid by positron emission tomography/computed tomography (PET/CT);
hence the technique can identify occult and advanced-stage disease, which helps avoid
unnecessary surgery. Tumor markers, such as carcinoembryonic antigen and carbohydrate
antigen19-9, are frequently elevated but considered non-diagnostic due to lack of specificity
(CA 19-9 92.7% versus 79.2% CEA) and sensitivity (CA 19-9 50% vs. 79.4% CEA). CEA
and CA 19-9 baseline tests are useful for monitoring response to therapy.[7] The preferred
staging system is TNM of the American Joint Committee on Cancer 2010 divided GC from
stage 0 to IV correlating strongly with a 5-year overall survival 81%, 50%, 29%, 7-8%, and
2-3%, respectively.[8]

Treatment / Management
Neoadjuvant therapy often is not an option due to the advanced disease at diagnosis and is not
considered a standard of care in resectable cases. Referral for early clinical trials should merit
consideration.[9]
Surgery is the only curative treatment for patients with Stage II or less and no
contraindications (see evaluation). Surgical resection of gallbladder cancer will include
cholecystectomy with a marginal hepatectomy with regional lymphadenectomy or common
bile duct resection (extended organs may require removal). For gallbladder cancer
incidentally found on cholecystectomy pathological specimen with stage T2 or higher, the
recommendation is to return for further exploration and re-resection.
Postoperative chemotherapy should be offered within 8 to 12 weeks and requires baseline
laboratory and imaging to re-stage disease before therapy initiation.[10] Adjuvant therapy
should be offered to patients with a resected pathological specimen report of T2 or higher,
node-positive, and margin positive, preferably for six months adjuvant chemotherapy (ACT)
or alternative four months with concurrent adjuvant chemoradiation (ACRT).[11]
The National Comprehensive Cancer Network (NCCN) consensus-based guidelines suggest
the following[12]:
1. Chemotherapy alone for six months with gemcitabine [1000 mg/weekly for three of
every four weeks] or 5-FU (fluoropyrimidine) [leucovorin 20 mg/m followed by FU
425 mg/m intravenous [IV] bolus days 1 through 5 every 28 days] published in the
ESPAC-3 trial with median overall survival for CT 43.1 months versus 35.2 months
 in the observation group without statistical significance (data extrapolated from
pancreaticobiliary malignancies).[13]
2. In addition to the above, another regimen includes four cycles of capecitabine (Cap)
[1,500 mg/m per day on days 1 to 14] plus gemcitabine (Gem) [1,000
mg/intravenously on days 1 and 8] every 21 days, followed by CRT [Cap 1330
mg/per day divided into two daily doses and RT 45 Gy to regional lymphatics; 54 to
59.4 Gy to tumor bed] published in a single-arm SWOG-S0809 trial with expected
medical outcomes (mOS) of 35 months without a comparison group.[11]
3. Lastly, 5-FU [225 mg/m daily]-based ACRT from other gastrointestinal malignancy
extrapolation data. At ASCO 2017, the BILCAP study was presented as first phase 3
randomized adjuvant therapy for patients with no post-surgical complications and
Eastern Cooperative Oncological Group of two or less (ECOG < 2), 447 patients were
randomized 1:1 Cap N 223[1250mg/m D1-14 every 21 days, for eight cycles] or
observation (Obs) N224 from 44 UK sites between 2006 to 2014, it included 18%
GC, and results showed an mOS for Cap 53mo when compared to observation for 36
months (HR 0.75 p0.028). Hence, Cap soon will be adopted as the new standard of
care.[14]
Surveillance by NCCN recommendations includes imaging every six months for two years, if
clinically indicated, then annually up to five years. Oncologists may monitor patients closely
with liver function test and tumor markers (CEA and CA19-9) every three to four months for
two years, then every six months up to five years. All other investigations can take place
when clinically indicated. 
Unresectable locally advanced and metastatic gallbladder cancers are candidates for palliative
goals/chemotherapy. Locally advanced may be managed with external beam radiation
therapy and usually involves a radiosensitizer, such as 5-FU, but this modality rarely will
achieve tumor control. Patients who are fit (ECOG 0-1) for chemotherapy could consider the
first-line option of Gem [1,000 mg/m] plus cisplatin (cis) [25 mg/m] on days 1 and 8 every
three weeks with acceptable toxicity as published in ABC-02 randomized trial which
included 148 patients with gallbladder cancer and had an mOS of 11.7 months in the
combination arm when compared to 8.3 months of Gem alone (HR, 0.70; p0.002).[15] Other
first-line gem-based combinations are not a randomized comparison, and single-arm studies
have reported an mOS for GemCap 12.7 months, Gem with Oxaliplatin 14.3 months both on
selected population or alternative 5-FU-based combination plus Cis 11.5 months or Cap 11.3
months.[16] Poor performance patients may receive a more tolerable, less toxic single oral
agent Cap with a reported mOS of 9.9 months, compared to the best supportive care of 4.5
months. All patients with advanced, unresectable disease should receive offers to participate
in clinical trials.

Differential Diagnosis
 Acalculous cholecystitis
 Acalculous cholecystopathy
 Ampullary carcinoma
 Bile duct strictures
 Bile duct tumors
  Biliary colic
 Biliary disease
 Biliary obstruction
 Cholangitis
 Cholecystitis

Prognosis
As stated above, the prognosis for gallbladder cancer is generally poor. Factors affecting the
prognosis is the stage at discovery, the specific location of the tumor, operability/response to
chemotherapy, and whether and where it has spread.[17] Gallbladder cancer has a high
recurrence rate and a poor 5-year survival rate. 

Complications
Complications of the disease include tumor recurrence, potentially causing visceral pain
resulting from intra-abdominal involvement. Regional recurrence can cause obstructive
jaundice. Clinicians should suspect recurrent disease in patients demonstrating unexplainable
weight loss, obstructive jaundice, or increasingly intense intra-abdominal pain.

Deterrence and Patient Education

Patients need to receive counsel appropriate to the stage of their disease. Whether the cancer
is caught early or is late-stage and inoperable, the patient and their families must understand
the likely outcomes. Psychological support is appropriate at all stages of this illness, and
clinicians should offer these services to the patient and the family.

Enhancing Healthcare Team Outcomes

While most problems with the gallbladder are relatively benign, rare gallbladder cancer (GC)
is a rare malignancy but represents almost 50% of all biliary tract cancer. Biliary cancers are
highly fatal malignancies. The healthcare team, including all clinicians and mid-level
practitioners, must be aware of the possibility of this untoward event in the workup of these
patients.